Patent GB-805886-A (GB)
Title: Improvements in or relating to new phenthiazine derivatives and processes for their preparation
Filed: 1956-11-09
Abstract: The invention comprises 3 - cyano - phenthiazines of the general formula <FORM:0805886/IV (b)/1> and salts and quaternary derivatives thereof (in which X represents -S-, -SO-, or -SO2-, B is a straight or branched chain divalent aliphatic hydrocarbon group containing from two to five carbon atoms, and which may be substituted by a group A-NR1R2 in which A represents a single bond or a -CH2-group, and R1 and R2 each represent an alkyl group containing up to five carbon atoms or one of them may also represent a hydrogen atom, or together with the connecting nitrogen atom they form a heterocyclic group, e.g. pyrrolidino, piperidino, morpholino, piperazino or 4-alkyl-piperazino); together with processes for their preparation by: (a) reaction of the corresponding 10-unsubstituted phenthiazine derivative with a haloamine Hal.B.NR1R2 (or its N-acyl derivative if R1 represents hydrogen, followed by hydrolysis) preferably in an aromatic hydrocarbon solvent and using as condensing agent a hydride, amide, hydroxide, alcoholate, alkyl, or aryl of an alkali metal; (b) condensation of an amine HNR1R2 with the phenthiazine derivative substituted in position 10 by -B1Y, wherein Y is the residue of a reactive ester, e.g. a halogen atom or a sulphuric or sulphonic ester residue, and B1 is a divalent hydrocarbon radical containing from two to five carbon atoms which may be substituted by a group -AY1(Y1 is the residue of a reactive ester or -NR1R2); (c) in the case where R1 and R2 do not form a hetero-ring, alkylation of the corresponding primary or secondary amines, e.g. with formaldehyde and hydrogen, using a hydrogenation catalyst, or by acylation and then reduction; (d) by decomposition of a phenthiazine-10-carboxylate of an amino alcohol HO-B-NR1R2 by heating it above 100 DEG  C., preferably between 150 DEG  and 220 DEG  C. either alone or in a diluent such as liquid paraffin, diphenyl, diphenyl oxide, quinoline, or o-dichlorobenzene; (e) cyclisation, preferably in a solvent, e.g. dimethyl formamide or dimethyl acetamide, or dimethylaniline, using an alkaline condensing agent (e.g. alkali metal hydroxide or carbonate) and preferably copper powder as catalyst, a compound of formula <FORM:0805886/IV (b)/2> (wherein one of Z1 and Z2 is a hydrogen atom and the other a cyano group); (f) when X represents sulphur, cyclisation with sulphur or a halo derivative thereof of 3-cyano-diphenylamine substituted on the amino group by -BNR1R2; (g) when X represents -SO- or -SO2-, by oxidation of the corresponding phenthiazine compounds, e.g. with H2O2 in the presence of acetic or nitric acid.  The starting materials may be optically active isomers or racemates, and in reactions (a) and (d) the processes may involve intramolecular rearrangement of the radical in the 10-position.  In examples: (1) to (6) 3-cyanophenthiazine in toluene is refluxed with sodamide and then 1-(4-methyl-1-piperazinyl)-3-chloropropane, the mixture treated with water and methane sulphonic acid, the aqueous phase basified and extracted with chloroform, giving 3-cyano-10-(3,41-methyl - 11 - piperazinylpropyl) - phenthiazine, characterized as its dihydrochloride; similarly are prepared the following 3-cyano-phenthiazines: 10-(3-dimethylaminopropyl)-, 10-(3-dimethylamino - 2 - methylpropyl)-, 10 - (2 - dimethylamino - 1 - propyl)-, 10 - (3,41 - methyl - 11 - piperazinyl - 2 - methyl - 1 - propyl) -, 10 - (1,3 - bis - dimethylamino - 2 - propyl) -, and their maleate salts; (7) to (11) 3-pyrrolidinyl-3-cyanophenthiazine-10-carboxylate is heated to 185-210 DEG  C. until evolution of CO2 ceases, residue in ethyl acetate extracted with methane sulphonic acid and extract basified, giving 3-cyano - 10 - (3 - pyrrolidinopropyl) - phenthiazine after chromatographic purification, and its hydrochloride salt; similarly are prepared the following 3-cyanophenthiazines: 10-(2-methyl-3 - pyrrolidinopropyl) -, 10 - (2 - diethylaminoethyl) -, 10 - (2 - diethylaminopropyl) -, 10 - (2,3 - dipiperidinopropyl) - and its ditartrate; (12) and (13) 3-(3-cyanophenthiazinyl)-propyl toluene p-sulphonate is autoclaved with ethylamine in toluene and the product converted to the acid maleate of 3-cyano-10-(3-monoethylaminopropyl) - phenthiazine; likewise 3 - (3 - cyano - 10 - phenthiazinyl) - propyl toluene p-sulphonate and piperidine give 3-cyano-10-(3-piperidinopropyl)-phenthiazine; (14) optically-active 3-cyano-10-(3-N-formyl-N-methylamino-2-methyl-1-propyl) -phenthiazine in methanol is refluxed with 4N HCl, giving 3-cyano-10-(3-monomethylamino - 2 - methyl - 1 - propyl) - phenthiazine, characterized as its maleate; (15) reduction of the last-named base in the presence of aqueous formaldehyde, aluminium chloride and Adams' catalyst yields 3-cyano-10-(3 - dimethylamino - 2 - methyl - 1 - propyl) - phenthiazine and its maleate; (16) and (17) describe the formation of the corresponding laevorotatory compounds; (18) 3-cyano-10-(2 - methyl - 3 - dimethylaminopropyl) - phenthiazine in acetic acid and sulphuric acid is oxidized with 34 per cent H2O2, giving 3-cyano-9,9 - dioxy - 10 - (2 - methyl - 3 - dimethylaminopropyl) - phenthiazine; (19) 2 - bromo - 21 - (3-dimethylamino - 2 - methylpropyl) - amino - 41 - cyano - diphenyl sulphide, potassium carbonate, copper powder and dimethyl formamide are refluxed to give 3-cyano-10-(3-dimethylamino - 2 - methylpropyl) - phenthiazine, characterized as its acid maleate.  3 - Pyrrolidinopropyl - 3 - cyanophenthiazine - 10-carboxylate is prepared by reacting 3-pyrrolidinopropanol with 3-cyanophenthiazine-10-carbonyl chloride, itself prepared by the action of phosgene on 3-cyanophenthiazine; 2-methyl-3-pyrrolidinopropyl-, 2-diethylaminoethyl-, 3-diethylamino - 2 - propyl -, and 1,3 - dipiperidino-2 - propyl - 3 - cyanophenthiazine - 10 - carboxylates are similarly prepared; 3-(3-cyano-10-phenthiazinyl)-propyl toluene-p-sulphonate is prepared from toluene-p-sulphonyl chloride and 3-cyano-10-(3-hydroxypropyl)-phenthiazine, itself prepared by acid hydrolysis of 3-cyano-10-(3-tetrahydropyranyloxypropyl)-phenthiazine, which is obtained by condensation of 1-tetrahydropyranyloxy-3-chloropropane with 3-cyanophenthiazine; optically active 3-cyano-10-(3-N-formyl - N - methylamino - 2 - methyl - 1 - propyl)-phenthiazine is prepared by condensation of the sodium derivative of 3-cyanophenthiazine with 3 - N - formyl - N - methylamino - 2 - methyl - 1 - chloropropane, obtained by the action of thionyl chloride on 3-N-formyl-N-methylamino-2-methyl-1-propanol, which is prepared from formamide and 3 - monomethylamino - 2 - methylpropanol, itself formed by lithium aluminium hydride reduction of optically active benzyl 3-mono-methylamino - 2 - methylpropionate obtained by resolution of the racemic form produced by transesterification of the methyl ester; 2-bromo-21 - (3 - dimethylamino - 2 - methylpropyl) - amino-41-cyanodiphenyl sulphide is prepared by condensation of 1 - chloro - 2 - methyl - 3 - dimethylaminopropane with 2-bromo-21-amino-41-cyanodiphenyl sulphide, itself prepared by iron-acetic acid reduction of 2-bromo-21-nitro-41-cyanodiphenyl sulphide, obtained by diazotization and cuprous bromide treatment of 2-amino-21-nitro-41-cyanodiphenyl sulphide, itself formed by condensation of 3-nitro-4-chlorobenzonitrile and 2-aminothiophenol.  Specification 805,887 is referred to.